Investigation of (E)‑3-[4-(2-Oxo-3-aryl-chromen-4-yl)oxyphenyl]acrylic Acids as Oral Selective Estrogen Receptor Down-Regulators

A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the di...

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Bibliographic Details
Published inJournal of medicinal chemistry Vol. 58; no. 8; pp. 3522 - 3533
Main Authors Degorce, Sébastien L, Bailey, Andrew, Callis, Rowena, De Savi, Chris, Ducray, Richard, Lamont, Gillian, MacFaul, Philip, Maudet, Mickael, Martin, Scott, Morgentin, Rémy, Norman, Richard A, Peru, Aurélien, Pink, Jennifer H, Plé, Patrick A, Roberts, Bryan, Scott, James S
Format Journal Article
LanguageEnglish
Published United States American Chemical Society 23.04.2015
Subjects
Administration, Oral
Animals
Cell Line, Tumor
Coumarins - chemistry
Coumarins - pharmacokinetics
Coumarins - pharmacology
Down-Regulation - drug effects
Estrogen Receptor alpha - analysis
Estrogen Receptor alpha - metabolism
Humans
Molecular Docking Simulation
Rats
Umbelliferones - chemistry
Umbelliferones - pharmacokinetics
Umbelliferones - pharmacology
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Summary:A novel estrogen receptor down-regulator, 7-hydroxycoumarin (5, SS5020), has been reported with antitumor effects against chemically induced mammary tumors. Here, we report on our own investigation of 7-hydroxycoumarins as potential selective estrogen receptor down-regulators, which led us to the discovery of potent down-regulating antagonists, such as 33. Subsequent optimization and removal of the 7-hydroxy group led to coumarin 59, which had increased potency and improved rat bioavailability relative to SS5020.
ISSN:0022-2623
1520-4804
DOI:10.1021/acs.jmedchem.5b00066